Loss of Matrix Metalloproteinase-2 Amplifies Murine Toxin-Induced Liver Fibrosis by Upregulating Collagen I Expression
- نوع فایل : کتاب
- زبان : انگلیسی
- مؤلف : Brian D. Radbill Ritu Gupta Maria Celeste M. Ramirez Analisa DiFeo John A. Martignetti Carlos E. Alvarez Scott L. Friedman Goutham Narl
- چاپ و سال / کشور: 2010
Description
Background and Aims Matrix metalloproteinase-2 (MMP-2), a type IV collagenase secreted by activated hepatic stellate cells (HSCs), is upregulated in chronic liver disease and is considered a profibrotic mediator due to its proliferative effect on cultured HSCs and ability to degrade normal liver matrix. Although associative studies and cell culture findings suggest that MMP-2 promotes hepatic fibrogenesis, no in vivo model has definitively established a pathologic role for MMP-2 in the development and progression of liver fibrosis. We therefore examined the impact of MMP-2 deficiency on liver fibrosis development during chronic CCl4 liver injury and explored the effect of MMP-2 deficiency and overexpression on collagen I expression. Methods Following chronic CCl4 administration, liver fibrosis was analyzed using Sirius Red staining with quantitative morphometry and real-time polymerase chain reaction (PCR) in MMP-2-/- mice and age-matched MMP-2?/? controls. These studies were complemented by analyses of cultured human stellate cells. Results MMP-2-/- mice demonstrated an almost twofold increase in fibrosis which was not secondary to significant differences in hepatocellular injury, HSC activation or type I collagenase activity; however, type I collagen messenger RNA (mRNA) expression was increased threefold in the MMP-2-/- group by real-time PCR. Furthermore, targeted reduction of MMP-2 in cultured HSCs using RNA interference significantly increased collagen I mRNA and protein, while overexpression of MMP-2 resulted in decreased collagen I mRNA. Conclusions These findings suggest that increased MMP- 2 during the progression of liver fibrosis may be an important mechanism for inhibiting type I collagen synthesis by activated HSCs, thereby providing a protective rather than pathologic role.
Dig Dis Sci (2011) 56:406–416 DOI 10.1007/s10620-010-1296-0 Received: 15 February 2010 / Accepted: 27 May 2010 / Published online: 19 June 2010
